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Clonal Variation in the B-Lineage Acute Lymphoblastic Leukemia Response to Multiple Cytokines and Bone Marrow Stromal Cells¹

Department of Laboratory Medicine/Pathology, University of Minnesota Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota 55455

The acquisition of genetic abnormalities in human B-lineage acute lymphoblastic leukemia (ALL) culminates in the clonal expansion of bone marrow (BM)-derived leukemic blasts. However, the response of leukemic cells to signals transduced by the BM microenvironment is not completely understood. The present study describes a new human B-lineage ALL cell line designated BLIN-4 (B LINeage-4). BLIN-4 cells respond to multiple cytokines/human BM stromal cell-derived molecules. One subline (BLIN-4E) undergoes cell death in the absence of BM stromal cells or cytokines and slowly proliferates on human BM stromal cells supplemented with interleukin (IL)-7 + FLT3-ligand. Another subline (BLIN-4L) slowly proliferates in the absence of cytokines and BM stromal cells and shows robust proliferation on BM stromal cells supplemented with IL-7 + FLT3-ligand. Although human BM stromal cells are comparable with IL-7 + FLT3-ligand in supporting proliferation of BLIN-4L cells, neutralizing antibody experiments demonstrate that BLIN-4L expansion on BM stromal cells is IL-7/FLT3-ligand independent. BLIN-4L could also respond to human thymic stromal lymphopoietin. BLIN-4E and BLIN-4L have the identical immunoglobulin heavy chain rearrangement and a CD10⁺/CD19⁺/CD20^-/CD22⁺/CD40⁺/µ heavy chain^- phenotype. The original BM leukemic blasts harbored a ring chromosome 4 with a low percentage of cells also having either trisomy 8 or trisomy 18. The BLIN-4 sublines maintained the ring chromosome 4, but the trisomy 8 and trisomy 18 segregated into BLIN-4E and BLIN-4L, respectively. Thus, the BLIN-4 sublines exhibit biological characteristics consistent with a potential evolution in B-lineage ALL involving subclones with decreasing requirements on the BM microenvironment.

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